Skin is subject to abuse by many extrinsic (environmental) factors as well as intrinsic factors. A common extrinsic factor is exposure to ultraviolet radiation. Whether extrinsic or intrinsic, the abuse results in skin aging. Skin aging happens in two ways: (1) through the natural aging process, which dermatologists call chronological aging (also known as chronoaging) and (2) through UV rays in sunlight accelerating the aging process, which doctors call photoaging. Chronoaging results in the thinning, loss of elasticity and general degradation of skin. As the skin naturally ages, there is a reduction in the cells and blood vessels that supply the skin. There is also a flattening of the dermal-epidermal junction, which results in weaker mechanical resistance of this junction. As a consequence, older persons are more susceptive to blister formation in cases of mechanical trauma or disease processes (Oikarinen et al., Photodermatal. Photoimmunol. Photomed., 7:3-4 (1990)).
By contrast, photoaging, or premature aging, is a process in which the skin changes in appearance as a result of repeated exposure to sunlight. Typically, photoaging occurs in areas of habitual exposure, such as the scalp, face, ears, neck, chest, forearms, and hands. The changes associated with photoaging include elastosis, atrophy, wrinkling, vascular changes (diffuse erythema, ecchymoses, and telangiectasias), pigmentary changes (lentigines, freckles, and areas of hypo- and hyper-pigmentation), and the development of seborrheic keratosis, actinic keratosis, comedones, and cysts. Glycation has been seen to be enhanced in photoaged skin (Jeanmaire C. et al., Br J Dermatol. 2001 July; 145(1):10-8).
As skin ages, there is an increase in oxidative stress, an increase in inflammation, a decrease in collagen levels, overexpression of the enzyme MMP, an increase in protein glycation, and an increase in mitochondrial decay. Additional aging processes include the intrinsic rate of proton leakage across the inner mitochondrial membrane, decreased membrane fluidity, and decreased levels and function of cardiolipin. The mitochondria, which create the energy the cells need by converting dietary and other cellular fuels into ATP, are adversely affected by these aging processes. It has been shown that oxidants generated by mitochondria are the major source of the oxidative lesions in the mitochondria that accumulate with age. (Ames B N, et al., Biochim Biophys Acta. 1995 May 24; 1271(1):165-70). As the skin ages, the mitochondria become severely impaired, and this leads to both a decrease in ATP production and greater oxidative damage.
There are currently numerous compositions on the market for the prevention and/or treatment of aging skin for both chronoaging and photoaging. However, there still remains a need for an effective topical anti-aging formulation that can be used, without a prescription, to treat the effects of oxidation and other skin damage.
Antioxidants are known to be useful agents in compositions for treating the skin. Additionally, substances to treat mitochondrial energy are useful as agents for treating the skin. For example, compositions for increasing ATP production and thereby treating aging skin are known. These include the administration of acetyl-L-carnitine. However, this treatment is a double-edged sword, since the acetyl-L-carnitine, in addition to increasing the ATP production, also increases mitochondrial free radicals and causes oxidative damage to the mitochondria. The supplementation of rats with acetyl-L-carnitine, in addition to improving mitochondrial function and increasing general metabolic activity lowered the hepatocellular antioxidant status. (Liu J, et al., Ann N Y Acad Sci. 2002, 959:133-66; Hagen T M, et al. Proc Natl Acad Sci USA 2002; 99(4):1870-5; Hagen T M, et al. Proc Natl Acad Sci USA 1998; 95:9562-6).
The use of lipoic acid in topical formulations is known. Perricone describes the use of lipoic acid, which may be combined with other agents such as ascorbic acid, or α-hydroxy acid, (U.S. Pat. No. 6,752,999), or applied to the skin to treat inflammation (U.S. Pat. No. 5,709,868). Streicher, in U.S. Pat. Pub. 2003/0190337 describes the use of R-lipoic acid in a topical formulation. U.S. Pat. Pub. 2004/0265345 teaches the topical application of a composition containing acetyl carnitine and lipoic acid. U.S. Pat. Pub. 2004/0219114 discloses a composition containing an R-lipoic acid, coenzyme Q-10, and acetyl-L-carnitine hydrochloride.
Other combinations have been taught as useful oral supplements, but not as applied to topical formulations. For example, the combination of acetyl-1-carnitine and R-α-lipoic acid for oral treatment of mitochondrial decay and RNA/DNA oxidation was shown by Liu J, et al. in Proc Natl Acad Sci USA 2002; 99(4):2356-61, and the oral administration of acetyl-1-carnitine and lipoic acid to rats is known to improve metabolic function similar to the administration of acetyl-L-carnitine, but also decrease oxidative stress. (Hagen T M, et al. Proc Natl Acad Sci USA 2002; 99(4): 1870-5). The effects of feeding mitochondrial metabolites (acetylcarnitine and lipoic acid) and mitochondrial antioxidants (alpha-phenyl-N-t-butyl nitrone and N-t-butyl hydroxylamine) to rats on the age-associated mitochondrial decay of the brain has been shown to provide an improved age-associated decline of ambulatory activity and memory, partially restore mitochondrial structure and function and elevate the levels of antioxidants. (Liu J, et al., Ann N Y Acad Sci. 2002, 959:133-66). The combination of lipoic acid, acetyl-L-carnitine, and carnosine has been described as useful as an oral supplement for “longevity” by Tim Batchelder, LE Magazine September 2003 (www.lef.org/magazine/-mag2003/sep2003_report_alpha—01.htm).
However, a topical formulation combining the advantageous properties obtained from combining a lipoic acid, a carnitine, and a carnosine has not been described. Therefore, it is needed to provide topical formulations useful in treating and protecting the skin.